Lung ischemia-reperfusion (IR) injury is a major complication after transplantation leading to higher post-operative mortality and late complications including chronic rejection. Our laboratory has established that early, acute lung IR injury is dependent on alveolar macrophage activation and TNF-alpha induction. One major anti-inflammatory mechanism in IR is mediated through the release of adenosine, and we have showed that activation of the A2A adenosine receptor (AR) reduces lung IR injury. Little is known about the role of other ARs in lung IR injury. Thus Aim 1 will determine the role of each AR in a mouse model of acute lung IR. Aim 2 will establish that A2AARs specifically on alveolar macrophages confer protection from acute lung IR injury. Aim 3 will determine if mechanisms of A2AAR attenuation of IR injury involve MAPK, NF-kB, and apoptosis pathways in macrophages. Our overall hypothesis is that specific activation of A2AARs on alveolar macrophages provides protection from post-transplant acute lung IR injury. PUBLIC HEALTH RELEVANCE: Lung reperfusion injury is a major complication of lung transplantation leading to higher post-operative mortality and late complications including chronic rejection. The objective of this proposal is to better understand the mechanisms of reperfusion injury and potentially prevent this complication. If successful, this will lead to more successful outcomes in lung transplantations and potentially increase the number of organs available to patients with end-stage lung disease.